G. Schellong

Definition of a standard‐risk group in children with AML

To define paediatric AML patients with a favourable outcome in order to design a risk‐adapted therapy, we analysed 489 children under 17 years of age treated similarly in studies AML‐BFM 83 and 87. 369 patients (75.4%) achieved remission. Estimated probabilities of survival, event‐free survival (EFS) and disease‐free survival (DFS) at 5 years were 50% (SE 2%), 43% (SE 2%) and 58% (SE 3%), respectively. Multivariate analysis revealed bone marrow blasts on day 15, morphologically defined risk groups and hyperleucocytosis to be of prognostic value. EFS at 5 years estimated for patients with 5% and >5% blasts on day 15 were 56% (SE 3%) v 27% (SE 4%); for the favourable morphological subgroups (M1/M2 with Auer rods, M3 and M4eo) it was 60% (SE 4%) compared with other patients (33%, SE 3%), P (Kaplan‐Meier)  =  0.0001 each. Hyperleucocytosis proved to be an independent prognostic factor, indicating a high risk, especially for early failure. The specific karyotypes t(8;21), t(15;17) and inv16 were closely related to the favourable morphology and outcome was in the same range. We conclude that for the definition of a standard‐risk group a combination of morphological and response criteria may be sufficient. The standard‐risk group defined by favourable morphology and a blast cell reduction on day 15 (not required for M3) comprises 31% of all patients, P survival, pEFS and pDFS at 5 years were 73% (SE 4%), 68% (SE 5%) and 76% (SE 4%), respectively.

Late valvular and other cardiac diseases after different doses of mediastinal radiotherapy for hodgkin disease in children and adolescents: Report from the longitudinal GPOH follow‐up project of the German–Austrian DAL‐HD studies

To analyze the impact of mediastinal irradiation on the incidence of cardiac late effects in long‐term survivors of pediatric Hodgkin disease (HD).

Early deaths due to hemorrhage and leukostasis in childhood acute myelogenous leukemia. Associations with hyperleukocytosis and acute monocytic leukemia.

There were 294 children with acute myelogenous leukemia (AML) entered into the German AML Berlin, Frankfurt, and Münster hospitals (BFM) 78 and 83 studies. Thirty (10%) died as a result of hemorrhage and/or leukostasis prior to or in the first 12 days of therapy. The risk of early death due to hemorrhage and/or leukostasis is significantly greater when certain features are initially present: acute monocytic leukemia (French‐American‐British [FAB] M5), hyperleukocytosis (⩾100,000/μl), and extramedullary organ involvement (P < 0.001). The risk increases sharply when these factors exist in combination: 72% mortality with FAB M5 and hyperleukocytosis, and 43% with FAB M5 and extramedullary organ involvement. In 11 patients leukostasis alone or in combination with hemorrhage was probably the cause of death during the first 3 days after diagnosis. All 11 children presented with hyperleukocytosis and were classified as monocytic subtype FAB M4 or M5. After induction, a close temporal association between rapid blast reduction and occurrence of fatal hemorrhage was established in five patients. Thrombocytopenic hemorrhages were controllable and, therefore, responsible for death only in exceptional cases. It is difficult to avoid these early fatal complications with current therapeutic measures. Early exchange transfusion together with special supportive care may be useful.

Resection Alone in 58 Children With Limited Stage, Lymphocyte-predominant Hodgkin Lymphoma-Experience From the European Network Group on Pediatric Hodgkin Lymphoma

Lymphocyte‐predominant Hodgkin lymphoma (LPHL) is a rare, CD20‐positive, good prognostic lymphoma in children. Patients with early‐stage LPHL who underwent successful surgical lymph node resection alone have been reported. To clarify the optimum treatment strategy in children, European study groups were asked to report their experience of surgery alone used in the treatment of pediatric LPHL.

Treatment Strategy for Different Risk Groups in Childhood Acute Lymphoblastic Leukemia: A Report From the BFM Study Group

Development of effective treatment programs for childhood acute lymphoblastic leukemia (ALL) has led to marked improvement of prognosis. The proportion of patients remaining in first remission for at least 5 years is generally estimated to be in the range of 50% once remission is achieved (Frei and Sallan 1978: Riehm et al. 1980: Robison et al. 1980). Since remission rates have been shown to be 90%–95% with currently used induction therapy, successful induction of remission is no longer an essential problem. Nevertheless, the quality of remission is apparently unsatisfactory in about one-half of the patients, eventually resulting in recurrence of the disease. Predictors of outcome have been defined and include white blood count (WBC), sex, thymic involvement, central nervous system disease at diagnosis, immunologic markers, unfavorable age, and blast cell morphology (Dow et al. 1977; Henze et al. 1979; Mathe et al. 1971; Sallan et al. 1978: Simone et al. 1975: Wagner and Baehner 1979; Working Party on leukemia in Childhood 1978): but attempts to adapt the therapeutic strategy to the presence of factors associated with a poor prognosis have not been able to enhance significantly therapeutic results. The approach of the BFM study group with the concept of intensive multidrug remission induction gives hope for an overall 75 % relapse-free survival in childhood ALL.

Impact of Latent Epstein-Barr Virus Infection on Outcome in Children and Adolescents With Hodgkin's Lymphoma

PURPOSE The prognostic significance of latent Epstein-Barr virus (EBV) infection in Hodgkins lymphoma (HL) is debated controversially. Especially in the pediatric age group, no conclusive data are available. PATIENTS AND METHODS Eight hundred forty-two children and adolescents (median age, 13.7 years) from pediatric multicenter treatment studies HD-90 and HD-95 were studied for latent EBV infection in Hodgkins and Reed-Sternberg cells by immunostaining against latent membrane protein 1 (LMP-1). Results were compared with established risk factors. RESULTS Two hundred sixty-three patients (31%) were LMP positive. EBV infection correlated with sex (39% male v 23% female; P < .001), histologic subtype (69% mixed cellularity v 22% nodular sclerosis v 6% lymphocyte predominance; P < .001) and young age. With a median follow-up of 4.9 years, 820 patients (97%) are alive. Probability of overall survival at 10 years (+/- standard deviation) for EBV-negative and -positive patients was 98.1% +/- 0.6% and 95.1% +/- 1.4%, respectively (P = .017 by log-rank test). A negative effect of EBV infection became evident for patients with nodular sclerosis subtype Bennett II (P = .02), and those treated for advanced stages (P = .003). In multivariate analysis, LMP positivity was an independent factor for adverse outcome (RR = 3.08). Probability of failure-free survival (FFS) in LMP positive and negative patients was 89.1% +/- 2.3% and 84.1% +/- 3.9%, respectively (P = .86). CONCLUSION With effective combined treatment modalities in pediatric HL, latent EBV infection has no influence on FFS but is associated with an inferior overall survival in crucial subgroups.

Urinary excretion of the enantiomers of ifosfamide and its inactive metabolites in children.

SummaryThe precondition for the antineoplastic effect of ifosfamide (ifo) is the oxidation of the oxazaphosphorine ring system, which contains a chiral centre at the phosphorous atom. This “ring oxidation” leads to the formation of alkylating mustard via several steps. A second metabolic pathway produces the cytostatically inactive metabolites 2- and 3-dechloroethyl-ifosfamide (2-d- and 3-d-ifo). The urinary excretion of the optical isomers of unmetabolised ifo and of 2- and 3-d-ifo, which represents the amount of ifo that has not been activated, was investigated by capillary gas chromatography for 18 treatment cycles in 14 children on various therapeutic schedules. The total cumulative excretion in 12 completely sampled cycles ranged from 27% to 50% of the ifo dose. Between 14% and 34% of the dose could be detected as ifo; 9% to 29%, as 3-d-ifo; and 2% to 8%, as 2-d-ifo. At 24 h after the end of therapy, excretion was nearly complete. Without exception, slightly more R-ifo (53%–61%) than S-ifo was excreted. S-2-d-ifo (50%–73%) was the main 2-d-metabolite. S-3-d-ifo (deriving from R-ifo) predominated in 6 of 14 children and R-3-d-ifo, in 8. Enantiomer-specific excretion increased after the end of infusion (up to 73% for R-ifo and 27% for S-ifo). We demonstrated stereospecific metabolism of ifo in children, with two different patterns of side-chain oxidation being observed. There was no evidence of important stereospecific ring oxidation in most children. A benefit should not be expected from the therapeutic application of pure enantiomers.

Acute Lymphoblastic Leukemia: Current Status of Therapy in Children

The symptoms of acute lymphoblastic leukemia (ALL) — pallor, bleeding, and infection or erythro-, thrombo-, and granulocytopenia — are due to the massive accumulation of undifferentiated cells in the bone marrow. The purpose of therapy, therefore, is to eradicate these leukemic cells in all body compartments. Prolonged disease-free survival (and subsequent cure) depends on the rapidity and thoroughness of cytoreduction. Thus, curative efforts have evolved to their present form as aggressive combination chemotherapy.

Effective childhood cancer treatment: The impact of large scale clinical trials in Germany and Austria

In Germany and Austria, more than 90% of pediatric cancer patients are enrolled into nationwide disease‐specific first‐line clinical trials or interim registries. Essential components are a pediatric cancer registry and centralized reference laboratories, imaging review, and tumor board assistance. The five‐year overall survival rate in countries where such infrastructures are established has improved from <20% before 1950 to >80% since 1995. Today, treatment intensity is tailored to the individual patients risk to provide the highest chances of survival while minimizing deleterious late effects. Multicenter clinical trials are internationalized and serve as platforms for further improvements by novel drugs and biologicals. Pediatr Blood Cancer 2013;60:1574–1581.

Breast Cancer in Young Women After Treatment for Hodgkin’s Disease During Childhood or Adolescence: An Observational Study With up to 33-Year Follow-up

BACKGROUND The treatment of Hodgkins disease (HD; also called Hodgkins lymphoma) in children and adolescents with radiotherapy and chemotherapy leads to high survival rates but has a number of late effects. The most serious one is the development of a secondary malignant tumor, usually in the field that was irradiated. In women, breast cancer can arise in this way. METHOD Data on the occurrence of secondary breast cancer (sBC) were collected from 590 women who were treated in five consecutive pediatric HD treatment studies in the years 1978-1995 and then re-evaluated in a late follow-up study after a median interval of 17.8 years (maximum, 33.7 years). Information was obtained from 1999 onward by written inquiry to the participants and their treating physicians. The cumulative incidence of sBC was calculated by the Gooley method. RESULTS By July 2012, sBC had been diagnosed in 26 of 590 female HD patients; the breast cancer was in the irradiated field in 25 of these 26 patients. Their age at the time of treatment for HD was 9.9 to 16.2 years (the pubertal phase), and sBC was discovered with a median latency of 20.7 years after HD treatment (shortest latency, 14.3 years) and at a median age of 35.3 years (youngest age, 26.8 years). The radiation dose to the supradiaphragmatic fields ranged from 20 to 45 Gy. The cumulative incidence for sBC 30 years after treatment for HD was 19% (95% confidence interval, 12% to 29%). For women aged 25 to 45 in this series, the frequency of breast cancer was 24 times as high as in the corresponding normal population. CONCLUSION Women who were treated for HD in childhood or adolescence have an increased risk of developing breast cancer as young adults. The risk is associated with prior radiotherapy and with the age at which it was administered (the pubertal phase). Because of these findings, a structured breast cancer screening project for this high-risk group has been initiated in collaboration with the German Consortium for Hereditary Breast and Ovarian Cancer (Deutsches Konsortium für familiären Brust- und Eierstockkrebs).